Cooperativity Scale: A Structure–Mechanism Correlation in the Self-Assembly of Benzene-1,3,5-tricarboxamides

ConspectusThe self-assembly of small and well-defined molecules using noncovalent interactions to generate various nano- and microarchitectures has been extensively studied. Among various architectures, one-dimensional (1-D) nano-objects have garnered significant attention. It has become increasingly evident that a cooperative or nucleation–elongation mechanism of polymerization leads to highly ordered 1-D supramolecular polymers, analogous to shape-persistent biopolymers such as actin. With this in mind, achieving cooperativity in self-assembled structures has been actively pursued with significant success. Only recently, researchers are focusing on the origin of the mechanism at the molecular level in different synthetic systems. Taking a step further, a thorough quantitative structure–mechanism correlation is crucial to control the size, shape, and functions of supramolecular polymers, and this is currently lacking in the literature.Among a plethora of molecules, benzene-1,3,5-tricarboxamides (BTAs) provide a unique combination of important noncovalent interactions such as hydrogen bonding, π-stacking, and hydrophobic interactions, for self-assembly and synthetic ease. Due to the latter, a diverse range of BTA derivatives with all possible structural mutations have been synthesized and studied during the past decade, mainly from our group. With such a large body of experimental results on BTA self-assembly, it is time to embark on a structure–mechanism correlation in this family of molecules, and a first step toward this will form the main focus of this Account. The origin of the cooperative mechanism of self-assembly in BTAs has been ascribed to 3-fold intermolecular hydrogen bonding (HB) between monomers based on density-functional theory (DFT) calculations. The intermolecular hydrogen-bonding interaction forms the central premise of this work, in which we evaluate the effect of different moieties such as alkyl chains, and amino acids, attached to the core amides on the strength of intermolecular HB, which consequently governs the extent of cooperativity (quantified by the cooperativity factor, σ). In addition to this, we evaluate the effect of amide connectivity (C- vs N-centered), the role of solvents, amides vs thioamides, and finally the influence of the benzene vs cyclohexane core on the σ. Remarkably, every subtle structural change in the BTA monomer seems to affect the cooperativity factor in a systematic and rationalizable way.The take home message will be that the cooperativity factor (σ) in the BTA family forms a continuous spectrum from 1 (isodesmic) to <10^–6 (highly cooperative) and it can be tuned based on the appropriate modification of the BTA monomer. We anticipate that these correlations drawn from the BTA series will be applicable to other systems in which HB is the main driving force for cooperativity. Thus, the understanding gained from such correlations on a prototypical self-assembling motif such as BTA will aid in designing more complex systems with distinct functions

Supramolecular Platform Stabilizing Growth Factors

High concentrations of supplemented growth factors can cause oversaturation and adverse effects in <i>in vitro</i> and <i>in vivo</i> studies, though these supraphysiological concentrations are often required due to the low stability of growth factors. Here we demonstrate the stabilization of TGF-β1 and BMP4 using supramolecular polymers. Inspired by heparan sulfate, sulfonated peptides were presented on a supramolecular polymer to allow for noncovalent binding to growth factors in solution. After mixing with excipient molecules, both TGF-β1 and BMP4 were shown to have a prolonged half-life compared to the growth factors free in solution. Moreover, high cellular response was measured by a luciferase assay, indicating that TGF-β1 remained highly active upon binding to the supramolecular assembly. The results demonstrate that significant lower concentrations of growth factors can be used when supramolecular polymers bearing growth factor binding moieties are implemented. This approach can also be exploited in hydrogel systems to control growth factor release

Pathway Selection in Peptide Amphiphile Assembly

The nature of supramolecular structures could be strongly affected by the pathways followed during their formation just as mechanisms and final outcomes in chemical reactions vary with the conditions selected. So far this is a largely unexplored area of supramolecular chemistry. We demonstrate here how different preparation protocols to self-assemble peptide amphiphiles in water can result in the formation of different supramolecular morphologies, either long filaments containing β-sheets or smaller aggregrates containing peptide segments in random coil conformation. We found that the assembly rate into β-sheets decreases in the presence of a destabilizing “good” solvent like hexafluoroisopropanol (HFIP) and is affected by transient conditions in solution. Also the peptide amphiphile investigated spontaneously nucleates the β-sheet-containing filaments at a critical fraction of HFIP in water below 21%. Furthermore, β-sheet assemblies have a high kinetic stability and, once formed, do not disassemble rapidly. We foresee that insights into the characteristic dynamics of a supramolecular system provide an efficient approach to select the optimum assembly pathway necessary for function

Supramolecular Buffering by Ring–Chain Competition

Recently, we reported an organocatalytic system in which buffering of the molecular catalyst by supramolecular interactions results in a robust system displaying concentration-independent catalytic activity. Here, we demonstrate the design principles of the supramolecular buffering by ring–chain competition using a combined experimental and theoretical approach. Our analysis shows that supramolecular buffering of a molecule is caused by its participation as a chain stopper in supramolecular ring–chain equilibria, and we reveal here the influence of various thermodynamic parameters. Model predictions based on independently measured equilibrium constants corroborate experimental data of several molecular systems in which buffering occurs via competition between cyclization, growth of linear chains, and end-capping by the chain-stopper. Our analysis reveals that the effective molarity is the critical parameter in optimizing the broadness of the concentration regime in which supramolecular ring–chain buffering occurs as well as the maximum concentration of the buffered molecule. To conclude, a side-by-side comparison of supramolecular ring–chain buffering, pH buffering, and molecular titration is presented

Amplifying Chiroptical Properties of Conjugated Polymer Thin-Film Using an Achiral Additive

Chiral conjugated polymers bearing enantiopure side chains offer the possibility to harness the effect of chirality in organic electronic devices. However, its use is hampered by the low degree of circular polarization in absorption (<i>g</i>_abs) in most of the conjugated polymer thin-films studied. Here we demonstrate a versatile method to significantly increase the <i>g</i>_abs by using a few weight percentages of a commercially available achiral long-chain alcohol as an additive. This additive enhances the chiroptical properties in both absorption and emission by ca. 5–10 times in the thin-films. We envisage that the alcohol additive acts as a plasticizer which enhances the long-range chiral liquid crystalline ordering of the polymer chains, thereby amplifying the chiroptical properties in the thin-film. The application of this methodology to various conjugated polymers has been demonstrated

Efficient Routes to A₃B‑Type <i>meso</i>-(4-Carboxyphenyl) Porphyrin Derivatives

A₃B-type <i>meso</i>-(4-carboxyphenyl) porphyrins were prepared either by stepwise coupling of aniline substituents to <i>meso</i>-tetrakis­(4-carboxyphenyl) porphyrin (TCPP) or by utilizing its partially protected trimethyl ester derivative. We demonstrate the high utility of this building block, which can be synthesized in very good yields by microwave-assisted Me₃SnOH hydrolysis

From Molecular Structure to Macromolecular Organization: Keys to Design Supramolecular Biomaterials

In the past decade, significant progress has been made in the field of biomaterials, for potential applications in tissue engineering or drug delivery. We have recently developed a new class of thermoplastic elastomers, based on ureidopyrimidinone (UPy) quadruple hydrogen bonding motifs. These supramolecular polymers form nanofiber-like aggregates initially <i>via</i> the dimerization of the UPy units followed by lateral urea-hydrogen bonding. Combined kinetic and thermodynamic studies unravel the pathway complexity in the formation of these polymorphic nanofibers and the subtlety of the polymer’s design, while these morphologies are so critically important when these materials are used in combination with cells. We also show that the cell behavior directly depends on the length and shape of the nanofibers, illustrating the key importance of macromolecular and supramolecular organization of biomaterials. This study leads to new design rules that determine what factors are decisive for a polymer to be a good candidate as biomaterial

Self-Assembly of Hydrogen-Bonding Gradient Copolymers: Sequence Control via Tandem Living Radical Polymerization with Transesterification

Chiral 1,3,5-tricarboxamide (BTA)-functionalized copolymers with gradient, bidirectional gradient, and random sequence distributions were synthesized via tandem living radical polymerization (LRP) with in situ monomer transesterification to investigate the effects of the BTA sequence on self-folding/aggregation properties in organic media. Here, 2-ethylhexyl methacrylate (EHMA) as a starting monomer was polymerized with a ruthenium catalytic system in the presence of a chiral BTA-bearing alcohol (BTA-OH) and Ti­(O<i>i</i>-Pr)₄. By tuning the concentration and time of addition of the Ti catalyst, the transesterification rate of EHMA into a chiral BTA-functionalized methacrylate (BTAMA) was synchronized with LRP to produce EHMA/BTAMA gradient or bidirectional gradient copolymers. In contrast, faster transesterification than LRP gave the corresponding random copolymer. Circular dichroism spectroscopy and dynamic light scattering performed on solutions of all BTA-functionalized copolymers indicated that the chiral BTA pendants self-assemble helically via hydrogen-bonding interaction in 1,2-dichloroethane, methyl­cyclohexane (MCH), and their mixtures to form single-chain or multichain polymeric nanoparticles. The temperature-dependent self-assembly behavior of the BTA pendants was virtually independent of the sequence distribution, whereas the size of the resultant nanoparticles depended on the sequence as follows: random < gradient < bidirectional gradient in MCH

Supramolecular Loop Stitches of Discrete Block Molecules on Graphite: Tunable Hydrophobicity by Naphthalenediimide End-Capped Oligodimethylsiloxane

The noncovalent functionalization of surfaces has gained widespread interest in the scientific community, and it is progressively becoming an extremely productive research field offering brand new directions for both supramolecular and materials chemistry. As the end-groups often play a dominant role in the surface properties obtained, creating loops with end-groups only at the surface will lead to unexpected architectures and hence properties. Here we report the self-assembly of discrete block moleculesstructures in-between block copolymers and liquid crystalsfeaturing oligodimethylsiloxanes (ODMS) end-capped with naphthalenediimides (NDIs) at the 1-phenyloctane/highly oriented pyrolytic graphite (1-PO/HOPG) interface. These structures produce unprecedented vertically nanophase-separated monolayers featuring NDI moieties that regularly arrange on the HOPG surface, while the highly dynamic ODMS segments form loops above them. Such arrangement is preserved upon drying and generates hydrophobic HOPG substrates in which the ODMS block length tunes the hydrophobicity. Thus, the exact structural fidelity of the discrete macromolecules allows for the correlation of nanoscopic organization with macroscopic properties of the self-assembled materials. We present a general strategy for tunable hydrophobic coatings on graphite based on molecularly combining crystalline aromatic moieties and immiscible oligodimethylsiloxanes

Sticky Supramolecular Grafts Stretch Single Polymer Chains

The folding of single polymeric chains into single chain polymeric nanoparticles (SCPNs) is a unique strategy to prepare ordered structures at the nanoscopic level. Structure forming elements are attached to a polymer chain designed to fold it into a well-defined object, the SCPN. The self-assembly of these units has been investigated in great detail. However, little is known about the impact of the resulting secondary structure on the conformation of the polymer chain. Here we employ a combination of scattering methods and spectroscopy to study how pendant chiral benzene-1,3,5-tricarboxamides (BTAs) fold oligo­(ethylene glycol) methyl ether methacrylate-based polymers into SCPNs. Circular dichroism spectroscopy shows that the extent of BTA self-assembly on the polymer chain in water can be fine-tuned by means of temperature and cosolvent addition (isopropanol). Small-angle neutron scattering experiments demonstrate that single polymer chains have an asymmetric shape with a constant cross section, <i>R</i>_cs, and variable length, <i>L</i>, with <i>L</i> > <i>R</i>_cs. The polymer chain extends and shortens in response to variations in temperature and solvent composition, which also influence the self-assembly of the BTA units. The SCPNs stretch upon association and shrink upon disassociation of the grafted supramolecular moieties